Carboplatin Plus Cytarabine in the Treatment of High-Risk Acute

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Leukemia (1999) 13, 161–165  1999 Stockton Press All rights reserved 0887-6924/99 $12.00 http://www.stockton-press.co.uk/leu Carboplatin plus cytarabine in the treatment of high-risk acute myeloblastic leukemia L Larrea, JA Martıńez, GF Sanz, G Martıń, J de la Rubia, C Jimeńez, I Jarque, A Cid, A Lo´pez and MA Sanz

Hematology Service, University Hospital La Fe, Valencia, Spain

Thirty-one patients (20 male and 11 female; median age 51 In this report we show the results obtained in a series of years (16–79)) with high-risk acute myeloblastic leukemia 31 patients with high-risk AML with a chemotherapy regimen (AML) (20 refractory AML and 11 secondary AML (s-AML) (four to myelodysplastic syndrome, five to chemo/radiotherapy, one combining CBDCA and intermediate-dose Ara-C. to aplastic anemia and one blastic chronic myelogenous leukemia (B-CML)) were treated with CBDCA (300 mg/m2/day ؋ 5 days in continuous i.v. infusion) plus intermediate-dose Ara-C mg/m2/day ؋ 3 days in rapid i.v. infusion). Nine patients Materials and methods 500) (29%) achieved CR (five s-AML (three myelodysplastic syndromes, one CML and one ALL) and four refractory AML) and Patient selection 11 patients had resistant disease. There were 11 early deaths (35%). Median disease-free survival of the nine responders was 4 months. The main toxicity was hematological, febrile epi- Eligibility criteria for the study included AML that had failed sodes took place in nearly all the patients (96%). The CBDCA induction remission, or had relapsed shortly (less than 12 plus Ara-C regimen showed an evident antileukemic activity in months) after a first remission, blastic phase of CML and AML high-risk leukemia. However, the lack of long-term disease-free survivors shows the need for innovative postremission stra- evolving from myelodysplastic syndromes and therapy- tegies. The high initial response rate seen in AML secondary related AML. to myelodysplastic syndromes (MDS) warrants further investigation of CBDCA in combination regimens for MDS patients. Keywords: acute myeloblastic leukemia; salvage therapy; carboplatin; high-risk AML Therapeutic protocol

Treatment consisted of CBDCA (300 mg/m2/day × 5 days Introduction administered as a continuous 24 h i.v. infusion) plus intermediate-dose Ara-C (500 mg/m2/day × 3 days, in 2 h i.v. Approximately 30% of adult patients with acute myeloblastic infusion). leukemia (AML) fail to obtain a complete remission and 60– 70% of those who achieve CR relapse within 2 years.1,2 The prognosis of refractory leukemia is poor.3–10 In an attempt to overcome this feature, salvage therapy tends to be more inten- Definitions sive than standard induction therapy using, when possible, higher dose or other non cross-resistant drugs not previously Although there are some controversies about the definition of delivered. These kind of treatments are also used as first-line refractory leukemia, the term of refractory AML has recently therapy in other high risk leukemia, such as in the setting of been defined as disease that responded to initial therapy for secondary AML (s-AML). less than 2 years or that failed to respond to this therapy.22 Carboplatin (CBDCA) is a second-generation platinum drug, Secondary leukemia usually refers to leukemia that arises which, unlike other platinum compounds like cisplatin, has secondary to chemo- or radiotherapy (treatment-related less nephrotoxicity and ototoxicity, with a dose-limiting tox- leukemia), environmental or occupational exposure to several icity represented by myelosuppression.11 In phase I–II trials, agents (eg benzene), and antecedent myelodysplasia.23 CR CBDCA in continuous infusion has showed an evident anti- was defined according to the criteria established by the Can- leukemic activity in the treatment of high-risk AML with cer and Leukemia Group B.24 Failures were classified as resist- acceptable toxicity, mainly hematological.12–20 In our pre- ant leukemia and early death. Early death was defined as viously reported experience,12,13 CBDCA as a single agent or death during induction therapy, or during the period of aplasia in combination with etoposide led to a 30% and 40% com- after chemotherapy. Toxicities were graded according to the plete remission (CR) rate, respectively. Some studies have WHO criteria.25 Overall survival was calculated from the date demonstrated an increasing activity of Ara-C, one of the most of start of chemotherapy until death or last follow-up. The dur- active drugs in acute leukemia treatment, with the addition of ation of disease-free survival was calculated from the time CR platinum analogues.21 Moreover, leukemic cells exhibiting the that was obtained until relapse, death in remission or last mdr1 phenotype or impaired intracellular levels of cytosine follow-up. arabinoside (Ara-C) would still manifest sensitivity to the phar- macological effects of CBDCA, as has been clinically shown in a pilot study using CBDCA as augmentation of standard leukemia induction therapy with daunorubicin and Ara-C.15 Statistical methods

Actuarial curves for disease-free survival and overall survival were plotted according to the Kaplan–Meier method.26 Stat- Correspondence: MA Sanz, Servicio de Hematologı´a, Hospital Univ- ersitario La Fe, Av. Campanar 21, 46009 Valencia, Spain; Fax: 34 6 istical analyses were carried out using the SPSS (Statistical 386 8757 Package for Social Science) package, version 6.0 for Received 19 May 1998; accepted 20 October 1998 Windows. Carboplatin plus cytarabine in the treatment of high-risk AML L Larrea et al 162 Table 1 Response to induction

No. of patients CR (%) Resistant disease (%) Early deaths (%)

Overall group 31 9 (29) 11 (35) 11 (35) Refractory AML 20 4 (20) 7 (35) 9 (45) s-AML 11 5 (45) 4 (36) 2 (18)

Results cases), new salvage chemotherapy after early relapse (two cases) and no further therapy (two). Six out of eight valuable Patient characteristics patients have relapsed. Of the two remaining patients, one died in remission from a secondary astrocytoma and the other From May 1992 to June 1996, 31 patients with high-risk AML is still alive and disease-free (42 m+). These two last patients entered in this study. Twenty patients were male and 11 had received an allogeneic stem cell transplantation shortly female; with a median age of 51 years (16–79). Twenty had after CR had been achieved with CBDCA plus Ara-C. The refractory AML and 11 had s-AML (four to MDS, ﬁve to median overall survival was 3 months (Figure 2). Median sur- chemo/radiotherapy, one to aplastic anemia and one blastic vival of patients who achieved CR and those that were refrac- chronic myelogenous leukemia (B-CML). Primary resistant or tory for salvage therapy was 15.5 and 2 months respectively relapsed AML had previously been treated with different pro- (Figure 3; P = 0.0002). tocols based on the classical combination of anthracycline plus cytarabine in a ‘7+3’ schedule.

Treatment outcome Toxicity

Treatment results are summarized in Table 1. Nine patients (29%) achieved CR, ﬁve s-AML (three MDS, one CML and The main toxicity was hematological. All patients developed one ALL) and four refractory AML. Among failures, 11 patients pancytopenia during therapy. The median length of neutro- had resistant disease and 11 were early deaths (35%) due to penia (neutrophil count Ͻ1 × 109/l) and thrombocytopenia infection (seven patients) and multiorgan failure (four (platelets Ͻ50 × 109/l) was 27 and 31 days, respectively. patients). The CR rate in refractory AML was 4/20 (20%) with Febrile episodes took place in nearly all the patients (96%). two CR occurring in eight relapsed AML patients (25%) while Major hemorrhage occurred in two patients (massive gastro- only two in 12 primary resistant AML patients (17%). The intestinal bleeding and hemoptisis). Minor episodes of highest CR rate corresponded to AML evolving from MDS hemorrhage occurred in 20 patients (epistaxis, hematuria and (3/4; 75%) whereas only one patient entered CR in the treat- gingival bruising). ment-related AML group (16%). The median disease-free sur- Extramedullary toxicity was characteristic of platinum vival of the nine responders was 4 months (Figure 1). derivatives, especially renal toxicity, observed in 11 patients One patient, 4 months after achieving CR, went abroad (to (eight grade 1, two grade 2 and one grade 3). Seventeen Argentina, where she lived) and was lost to follow-up. Several patients had skin rashes. Almost all patients had nausea and therapeutic approaches were made after achieving CR: auto- vomiting. Only six patients had mild mucositis and 19 had logous hematopoietic stem cell transplantation (two cases), diarrhea. In 19 patients altered hepatic tests were seen. Tox- allogeneic hematopoietic stem cell transplantation (two icities are shown in Table 2.

Figure 1 Actuarial disease-free survival for patients achieving CR. Carboplatin plus cytarabine in the treatment of high-risk AML L Larrea et al 163

Figure 2 Overall group survival.

Figure 3 Survival of the responders to salvage therapy.

Table 2 Toxicities infusion etoposide/CBDCA regimen. Comparing our previous experience,12,13 employing CBDCA alone or in combination Grade with etoposide, the addition of Ara-C to CBDCA in a high-risk treatment schedule did not result in a higher CR rate (Table 3) 01234 and was associated with higher toxicity. Looking for differ- ences in the CR rates in the different disease groups, CBDCA Infection 1 11 1 16 2 in combination both with etoposide and Ara-C yields better Skin 14 12 5 — — Mucositis 25 3 3 — — results than CBDCA alone for secondary AML, especially for Vomiting 4 3 16 4 4 myelodysplastic syndromes (75% vs 28.5% CR rate). With Diarrhea 12 7 9 3 regard to refractory AML the combination with etoposide Liver 12 10 3 5 1 shows the best CR rates (47%), followed by CBDCA alone Hyperglycemia 24 5 1 1 (33%), while the addition of Ara-C to CBDCA gives the poor- est results (20%). = = WHO criteria for infection: 0 no, 1 microbiological with bacteri- Another topic of concern with this population of patients ema; 2 = microbiological without bacteriemia, 3 = clinical, 4 = FUO. with high-risk AML is the short duration of remissions (4 months in our series). Regarding the approaches to prolong Discussion the length of remission, there is no consensus about the postremission therapy in high-risk AML. There are several studies The therapeutic results of CBDCA-containing regimens in reporting a number of patients gaining long-term disease-free AML, reported in the literature reﬂect an enormous variation. survival after allogeneic hematopoietic stem cell transplan- Letendre et al,27 obtained no response with a continuous tation.28,29 In our series, this procedure was performed in two Carboplatin plus cytarabine in the treatment of high-risk AML L Larrea et al 164 Table 3 Characteristics of patients with high-risk AML and treated with CBDCA regimens

Carboplatin12 Carboplatin/etoposide13 Carboplatin/Ara-C

No. patients 27 20 31 Sex M/F 16/11 13/7 20/11 Age (year) median (range) 50 (16–71) 43 (20–67) 51 (16–79) Response to induction: CR/failure (%) 8/19 (30) 8/12 (40) 9/22 (29) Primary resistant AML/CR (%) 6/2 (33) 8/3 (37.5) 12/2 (17) Relapsed AML/CR (%) 3/2 (33) 3/1 (33) 8/2 (25) Secondary to MDS/CR (%) 7/2 (28.5) 4/3 (75) 4/3 (75) Treatment-related AML/CR (%) 2/0 0 6/1 (16) B-CML/CR (%) 9/2 (22) 5/1 (20) 1/1 (100)

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